1. Field of the Invention
The present invention relates to a pharmaceutical preparation adhering to the skin, in particular a transdermal therapeutic system, for the release of 17-.beta.-estradiol and optionally further active substances through the skin to the human organism.
Pharmaceutical preparations contacting the skin include, for example, ointments, creams, lotions, and also drug-containing patches, these have been introduced on the market for some time under the name "transdermal therapeutic systems" (TTS) to treat several diseases.
In the meantime, TTSs comprising the active substance 17-.beta.-estradiol have also been on the market as a therapeutic agent for climacteric complaints, and, for a short time, also against osteoporosis, proving successful in therapy.
In several cases, however, the insufficient capability of the active substance to permeate through the skin has become apparent as a disadvantage of prior art systems. This cannot be increased beyond a certain limit, the so-called "saturation flow", although numerous galenic measures with respect to the TTS-construction have been taken (use of multilayer systems, use of controlling membranes, variations of the active substance concentration, modification of the base polymer, and the like).
2. Description of the Related Art
The finding that the transdermal flow of an active substance from the solid, finely dispersed phase cannot be increased further, even if high-dissolving vehicles are used, can already be found in the trailblazing works of Higuchi (e.g., T. Higuchi: Physical Chemical Analysis of percutaneous absorption process from creams and ointments, J. Soc. Cosmetic Chem. 11, p. 85-97 (1960). However, for many active substances there is the possibility of adding so-called "enhancers" to the TTS during its production. In general, these are liquid additives improving the absorption properties of human skin so that the active substance can be absorbed from a sufficiently small TTS-surface.
In particular readily volatile enhancers, e.g., ethanol frequently used for the active substance 17-.beta.-estradiol, cause problems due to extreme softening of the patches' adhesive layers, therefore they require additional bulky compartments in the system, rendering the TTS unacceptably thick or voluminous. Finally, any additional non-polymeric additive involves the risk of intolerance phenomena on the skin, possibly even that of sensitization.
The addition of less volatile, however, mostly less active enhancers (e.g., glycerol esters, cyclic amides, eucalyptol) makes it possible to produce matrix systems comprising the active substance and absorption-promoting components in one or several monolithic layers. However, the adhesive strength of the patch remains unsatisfactory.
U.S. Pat. No. 4,863,738 represents one of many examples claiming the application of an active substance, e.g., 17-.beta.-estradiol, together with an enhancer (in this case glycerol monooleate) in an optional concentration within a TTS-matrix.
According to the art, these TTSs do not permit a satisfactory therapy, either because the chosen enhancers have a poor skin tolerance, or the systems must have unacceptably large surfaces owing to insufficient active substance flow through the skin.
Dissolving more active substance molecularly disperse in the TTS than corresponds to the saturation solubility might be another possibility of increasing the active substance flow through the skin. With the degree of supersaturation of these systems the permeation rate through the skin is increased to the same extent. However, since supersaturated physical states are thermodynamically unstable, these forms of administration are not stable in storage. Spontaneous, unforeseeable precipitations of active substance particles will take place within months, or not later than years, so that the flow rate through the skin gradually decreases to the saturation flow level and a great deal of the initially existent therapeutic activity is lost.
The systems described in EP 0 421 454 comprise 17-.beta.-estradiol in an acrylate polymer under addition of "crystallization inhibitors" and tackifying resins. Swelling agents are contained to give protection against premature loss of adhesive force.
A completely different way of avoiding thermodynamic instability is opened up in DE 42 37 453. It describes a transdermal therapeutic system having an active substance concentration ranging between the saturation solubility under moist conditions and that under dry conditions. A maximum ambient humidity of 10% is meant by "dry" conditions, and the achieved increase of skin permeation is stated to be about 50%.